The long-term objective of this application is to regenerate a patient-specific temporomandibular joint (TMJ) condyle using a process free of solvents, particulates and polymerization initiators. In a broader sense, this technology can be readily applied to orthopaedic applications or any other tissue engineering application with complex macroscopic shape requirements. However, because the TMJ has been conspicuously excluded from the progress of the orthopaedic community, and with severely afflicted TMJ patients in agonizing pain and despair, we have selected the TMJ as the prioritized focus of our attention. The first step toward our long-term objective will be to develop a novel condyle-shaped bone construct. Therefore, the objective of this proposal will be to use a novel stem cell source together with a supercritical fluid approach to engineer bone in a predetermined shape. Since pressurized CO2 melts poly(lactic-co-glycolic acid) (PLGA) at ambient temperatures, PLGA expands as the pressure is released and CO2 escapes, as champagne does when the cork is popped on a shaken bottle, except the PLGA foam solidifies when the pressure is released. We hypothesized that we could take advantage of this phenomenon by allowing the PLGA to expand into a mold to give it a pre-determined shape when it solidified. Indeed, our preliminary testing confirmed this hypothesis, introducing a new application for CO2 foaming: as an alternative approach for producing shape-specific scaffolds in tissue engineering. Our overall strategy in this proposal is to expose human umbilical cord matrix stem cells (HUCMSCs) to osteogenic factors in a condyle-shaped, foamed PLGA scaffold. Our chief hypothesis is that osteo-induced HUCM stem cells, combined with a novel supercritical fluid scaffold foaming approach, will result in a shape-specific engineered TMJ condyle. To test this hypothesis, we propose the following specific aims: 1) to develop and characterize the supercritical CO2 scaffold fabrication technique, 2) to engineer bone plugs using CO2-foamed poly(lactic-co-glycolic acid) (PLGA) scaffolds, and 3) to engineer a shape-specific TMJ condyle bone construct. The proposed research presents a layering of innovative approaches to musculoskeletal tissue engineering by utilizing an exciting new cell source, and taking an existing technology (scaffold foaming) in an original direction as a new method to create shape-specific scaffolds. This application will ultimately be a logical candidate for translational research, with a human cell source, an FDA-approved biomaterial, and an environmentally friendly, cost-effective fabrication process. The long-term vision is for patient-specific molds to be created from CT images, with HUCMSCs available from a cord cell bank or conceivably even from the patient's own cryopreserved HUCMSCs. Realization of our long-term goal would revolutionize TMJ treatment, restoring structure and function to TMJs ravaged by disease (e.g., arthritis, cancer) and trauma, and bringing hope to the millions of Americans suffering from TMJ disorders. PUBLIC HEALTH RELEVANCE: Disorders of the temporomandibular joint (TMJ), commonly known as the jaw joint, affect more than 10 million Americans, causing agonizing pain and difficulty in simple activities such as eating, talking, and yawning. An exciting potential solution is tissue engineering, which aims to replace TMJ structures ravaged from trauma and disease. This research plan describes an environmentally benign and novel approach to regenerate anatomically correct TMJ structures.